Particle/Protein Interaction and Migration via Anisotropic Membrane Deformation

通过各向异性膜变形实现颗粒/蛋白质相互作用和迁移

• 批准号: 1133267
• 负责人: Kathleen Stebe
• 金额: $ 20万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1133267&HistoricalAwards=false
• 关键词: Particle; Protein; Interaction; Migration; via

1133267StebeIntellectual Merit: Proteins associated with lipid membranes interact, migrate and assemble. One mode of interaction is mediated by deformations created by proteins in the membrane. Proteins create these distortions or inclusions by insertion in lipid bilayers or by association with the membrane by adhesion. The proteins are then free to move laterally in the lipid bilayers, propelled by energy stored in the membrane deformation. Similarly, nanoparticles can attach to or insert in membranes, creating inclusions that decay with distance from the particle. The PIs will study interactions between anisotropic inclusions on membranes with complex topography. On this level, proteins/ particles are treated equivalently as entities that change the local shape of the membrane. The inclusions create excess energy by bending and straining the membrane. When neighboring deformation fields overlap, the energy of the membrane depends on article/protein orientation and distance. In addition, when isolated inclusions occur on membranes with complex topography, the inclusions migrate to preferred locations. These interactions occur over a characteristic length related to the membrane tension and bending rigidity that is typically between 10-100nm. Particle/protein shape and energy anisotropy should play a key role in these interactions that has not been addressed beyond the level of point disturbances. Thus, preferred orientations, repulsions, and attractions have not been explored as a function of inclusion shape. Harnessing the interplay of inclusion geometry, interaction, and orientation would provide a powerful assembly tool.The motivating idea in the current literature is that proteins of different shapes are curvature inducers, creating inclusions with characteristic principle radii. These inclusions act as curvature sensors, and will migrate to the equilibrium position at which their intrinsic radii of curvature match optimally those of the host membrane. Thus, proteins with plate like structures prefer relatively planar locations,rod-like structures prefer tethers, bent plates prefer locations of like curvature, and saddle-like shapes prefer membrane necks. While this general concept is gaining traction, analyses have thus far addressed only weakly non-circular inclusions in the limit of weak deformations assuming linear superposition. The researchers propose to study anisotropic inclusions to understand their migration and orientation to sites of preferred curvature, and their pair interactions, as a function of membrane tension and rigidity. They will use analysis and simulation based on a mesoscale description of the membrane free energy in terms of a Helfrich model to predict protein/membrane interactions for canonically shaped inclusions with associated excess curvatures and areas. Deterministic interactions will be studied using analysis and simulation in terms of the Helfrich model including membrane bending and tension. Non-deterministic interactions will be simulated by accounting for entropic interactions in a Helfrich Monte Carlo (MC) model developed by the co-PI Radhakrishnan. While they focus on mesoscale interactions, they will relate the work to the ongoing molecular-scale simulations of protein-membrane interactions in the Radhakrishan group. Their aim is to establish rules for particles/proteins on curved and stretched membranes. How does an inclusion with a given aspect ratio and bending interact within the membrane. How do pairs interact Canonical, highly anisotropic inclusion shapes will be studied using simulation and analysis. Their collaborator, Prof. Tobias Baumgart, will check predictions in experiment.Broader Impacts Scientific/ Technological: This work will provide predictions to direct assembly of proteins/particles in membranes. Anisotropic assembly within biomembranes or biomimetic systems of particles or proteins hold untapped promise to engineer new oriented assemblies, to influence vesiculation and budding events, to promote uptake of therapeutic or nanoparticle contrast agents, and to gain insight into viral docking to host cells during an infection. Mentoring of Female and Under-represented Students: Students from outreach initiatives will be welcome to work on small research projects associated with this research. (PI's personal contacts, Project SEED, REU programs). Stebe regularly speaks in forums concerning women and minorities in engineering and has extensive experience in directing research experiences for highschool and undergraduate students, often femake or from under-represented groups. (AWE at Penn, and external venues). Radhakrishnan Student Participation: Postdoctoral mentoring: Postdoctoral career development is a priority in the Stebe and Radhakrishnan groups.

1133267Stebeintlectual Fure：与脂质膜相关的蛋白质相互作用，迁移和组装。一种相互作用的方式是由膜中蛋白质产生的变形介导的。蛋白质通过在脂质双层中插入或通过粘附与膜结合产生这些变形或夹杂物。然后，蛋白质可以自由在脂质双层中横向移动，该蛋白质由存储在膜变形中的能量推动。同样，纳米颗粒可以连接到膜中或插入膜，从而产生与距离粒子距离衰减的夹杂物。 PI将研究具有复杂地形的膜上各向异性夹杂物之间的相互作用。在此级别上，将蛋白质/颗粒等效地处理为改变膜局部形状的实体。夹杂物通过弯曲和拉紧膜创造过多的能量。当相邻的变形场重叠时，膜的能量取决于文章/蛋白质方向和距离。另外，当分离的夹杂物发生在具有复杂地形的膜上时，夹杂物迁移到首选位置。这些相互作用发生在与膜张力和弯曲刚度有关的特征长度上，通常在10-100nm之间。粒子/蛋白质形状和能量各向异性在这些相互作用中应发挥关键作用，而这些相互作用尚未超出点扰动的水平。因此，尚未探索首选方向，排斥和景点作为包容形状的函数。利用包含几何，相互作用和方向的相互作用将提供强大的组装工具。当前文献中的激励思想是，不同形状的蛋白质是曲率诱导者，创造具有特征性原理半径的包含物。这些夹杂物起到曲率传感器的作用，并将迁移到平衡位置，在该位置其固有的曲率半径最佳地匹配宿主膜的曲率。因此，具有板块结构的蛋白质更喜欢相对平面的位置，棒状结构更喜欢割伤，弯曲的板喜欢曲率的位置，而类似鞍形的形状则喜欢膜颈。尽管这种一般概念正在获得吸引力，但到目前为止，分析仅在假设线性叠加的弱变形极限下仅解决了弱的非圆周包含。研究人员建议研究各向异性夹杂物，以了解其迁移和取向首选曲率部位及其对相互作用，这是膜张力和刚性的函数。他们将根据helfrich模型对膜自由能的中尺度描述进行分析和仿真来预测蛋白质/膜的相互作用，用于与相关的过量曲率和区域的规范形状夹杂物的蛋白质/膜相互作用。确定性相互作用将使用分析和仿真来研究Helfrich模型，包括膜弯曲和张力。通过考虑由Co-Pi Radhakrishnan开发的Helfrich Monte Carlo（MC）模型中的熵相互作用，将模拟非确定性相互作用。当他们专注于中尺度相互作用时，他们将将工作与Radhakrishan组中蛋白质 - 膜相互作用的持续分子尺度模拟联系起来。他们的目的是在弯曲和拉伸的膜上制定颗粒/蛋白质的规则。给定纵横比和弯曲的包含在膜中如何相互作用。如何使用模拟和分析研究对将研究对规范，高度各向异性的包容形状的相互作用。他们的合作者Tobias Baumgart教授将检查实验中的预测。Broader对科学/技术的影响：这项工作将为直接组装膜中的蛋白质/颗粒提供预测。颗粒或蛋白质的生物膜或仿生系统内的各向异性组装对工程师的新定向组件有未开发的承诺，以影响囊泡和萌芽事件，以促进治疗或纳米粒子对比剂的吸收，并在感染过程中促进对宿主细胞的洞察力。对女性和代表性不足的学生的指导：欢迎来自外展计划的学生参加与这项研究相关的小型研究项目。 （PI的个人联系，项目种子，REU计划）。 Stebe定期在论坛上谈论有关工程领域的妇女和少数民族的演讲，并在指导高中和本科生的研究经验方面具有丰富的经验，通常是女性或代表性不足的群体。 （在宾夕法尼亚州和外部场地敬畏）。 Radhakrishnan学生参与：博士后指导：博士后职业发展是Stebe和Radhakrishnan群体的优先事项。